Identification and Validation of Prognostic Model for Tumor Microenvironment-Associated Genes in Bladder Cancer Based on Single-Cell RNA Sequencing Data Sets.

PURPOSE: The purpose of this study was to elucidate the relationship between the tumor microenvironment (TME) and cellular diversity in bladder cancer (BLCA) progression, leveraging single-cell RNA sequencing (scRNA-seq) data to identify potential prognostic biomarkers and construct a prognostic model for BLCA. METHODS: We analyzed scRNA-seq data of normal and tumor bladder cells from the Gene Expression Omnibus (GEO) database to uncover crucial markers within the bladder TME. The study compared gene expression in normal versus tumor bladder cells, identifying differentially expressed genes. These genes were subsequently assessed for their prognostic significance using patient follow-up data from The Cancer Genome Atlas. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses, focusing on eight genes of interest. The predictive performance of the model was also tested against additional GEO data sets (GSE31684, GSE13507, and GSE32894). RESULTS: The prognostic model demonstrated reliable prediction of patient outcomes. Validation through gene set enrichment analysis and immune cell infiltration assessment supported the model's efficacy. The results from both the univariate and multivariate analyses suggest that the risk score is an independent prognostic factor with a hazard ratio of 2.97 (95% CI, 2.28 to 3.9, P < .001). In the validation cohort, the AUC at 1, 2, and 3 years is 0.74, 0.74, and 0.72, respectively. CONCLUSION: Our findings proposed biomarkers with prognostic potential, laying the groundwork for future in vitro validation and therapeutic exploration. This contributes to a deeper understanding of the genes associated with bladder TME and may improve prognostic precision in BLCA management.

Appropriateness of Imaging for Low-Risk Prostate Cancer-Real World Data from the Pennsylvania Urologic Regional Collaboration (PURC).

Imaging for prostate cancer defines the extent of disease. Guidelines recommend against imaging low-risk prostate cancer patients with a computed tomography (CT) scan or bone scan due to the low probability of metastasis. We reviewed imaging performed for men diagnosed with low-risk prostate cancer across the Pennsylvania Urologic Regional Collaborative (PURC), a physician-led data sharing and quality improvement collaborative. The data of 10 practices were queried regarding the imaging performed in men diagnosed with prostate cancer from 2015 to 2022. The cohort included 13,122 patients with 3502 (27%) low-risk, 2364 (18%) favorable intermediate-risk, 3585 (27%) unfavorable intermediate-risk, and 3671 (28%) high-risk prostate cancer, based on the AUA guidelines. Amongst the low-risk patients, imaging utilization included pelvic MRI (59.7%), bone scan (17.8%), CT (16.0%), and PET-based imaging (0.5%). Redundant imaging occurred in 1022 patients (29.2%). There was variability among the PURC sites for imaging used in the low-risk patients, and iterative education reduced the need for CT and bone scans. Approximately 15% of low-risk patients had staging imaging performed using either a CT or bone scan, and redundant imaging occurred in almost one-third of men. Such data underscore the need for continued guideline-based education to optimize the stewardship of resources and reduce unnecessary costs to the healthcare system.

Heterogeneity in the Definitions of Proximal Junctional Kyphosis and Failure in Spinal Deformity Literature: A Tower of Babel.

STUDY DESIGN: Systematic review. OBJECTIVE: To describe the various definitions of PJK and PJF used in spinal deformity literature and their utility over time. SUMMARY OF BACKGROUND DATA: Proximal junctional kyphosis or failure (PJK/PJF) is among the most common complication after long-segment fusions, but there is no consensus on their definitions. This presents challenges in understanding risk factors, management, and prevention strategies. METHODS: A systematic literature review was performed on studies specifying a definition of PJK and/or PJF. PJK definitions were categorized as radiographic vs non-radiographic and data was collected on PJK criteria including threshold for proximal junctional angle (PJA), change in PJA, vertebra selection for PJA measurement, and follow-up timepoints. PJF definitions were categorized as structural failure, need for revision, symptomatic failure, and radiographic (angular). RESULTS: 359 studies defining PJK and/or PJF were identified. While 56% of studies used the definition PJA>10° and PJA change from baseline>10°, the remainder expressed significant heterogeneity with respect to criteria for magnitude of PJA and degree of PJA change. The most common vertebrae assessed were UIV/UIV+2 (74%) and most common minimum follow-up (mFU) listed was 2 years (60%). Mean FUs for studies varied considerably even in studies with the same mFU, from 2.1-8.9 years (2-year mFU) and 1.1-4.0 years (1-year mFU). PJF definitions were most commonly structural (58%) or defined as a need for revision (48%), with a much less common use of PJA thresholds (23%). CONCLUSIONS: The challenges faced in preventing proximal junctional complications are mired in the heterogenous groundwork by which PJK and PJF are defined. Most definitions of PJK use radiographic thresholds without consideration of clinical relevance and variations in individual alignment. Conversely, definitions of PJF are based on clinical criteria, which are often subjective. Future research should focus on understanding the mechanisms of PJK/PJF, as only then will we be able to accurately define and prevent these complications.

A Randomized, Controlled Trial Evaluating Perioperative Risk-Stratification and Risk-Based, Protocol-Driven Management After Elective Major Cancer Surgery.

OBJECTIVE: We evaluated the efficacy of risk-based, protocol-driven management versus (vs) usual management after elective major cancer surgery to reduce 30-day rates of postoperative death or serious complications (DSC) . SUMMARY BACKGROUND DATA: Major cancer surgery is associated with significant perioperative risks which result in worse long-term outcomes. METHODS: Adults scheduled for elective major cancer surgery were stratified/randomized to risk-based escalating levels of care, monitoring, and co-management vs usual management. The primary study outcome was 30-day rate of DSC. Additional outcomes included complications, adverse events, health care utilization, health-related quality of life (HRQOL), and disease-free and overall survival (DFS and OS). RESULTS: Between August 2014 and June 2020, 1529 patients were enrolled and randomly allocated to the study arms; 738 patients in the Intervention Arm and 732 patients in the Control Arm were eligible for analysis. 30-day rate of DSC with the intervention was 15.0% (95% CI, 12.5-17.6%) vs 14.1%, (95% CI, 11.6-16.6%) with usual management (P=0.65). There were no differences in 30-day rates of complications or adverse events (including return to the operating room); postoperative length of stay; rate of discharge to home; or 30, 60, or 90-day HRQOL or rates of hospital readmission or receipt of anti-neoplastic therapy between the study arms. At median follow-up of 48 months, OS (P=0.57) and DFS (P=0.91) were similar. CONCLUSIONS: Risk-based, protocol-driven management did not reduce 30-day rate of DSC after elective major cancer surgery compared to usual management, nor improve postoperative health care utilization, HRQOL, or cancer outcomes. Trials are needed to identify cost-effective, tailored perioperative strategies to optimize outcomes after major cancer surgery.

Association of circulating tumor DNA with patient prognosis in surgically resected renal cell carcinoma.

BACKGROUND: Despite complete resection, 20%-50% of patients with localized renal cell carcinoma (RCC) experience recurrence within 5 years. Accurate assessment of prognosis in high-risk patients would aid in improving outcomes. Here we evaluate the use of circulating tumor DNA (ctDNA) in RCC using banked samples and clinical data from a single institution. METHODS: The cohort consisted of 45 RCC patients (≥pT1b) who underwent complete resection. The presence of ctDNA in plasma was determined using a personalized, tumor-informed ctDNA assay (Signatera RUO, Natera, Inc.). Relationships with outcomes and other relevant clinical variables were assessed. The median follow-up was 62 months. RESULTS: Plasma ctDNA was detected in 18 out of 36 patients (50%) pre-operatively and was associated with increased tumor size (mean 9.3 cm vs. 7.0 cm, P < .05) and high Fuhrman grade (60% grades III-IV vs 27% grade II, P = .07). The presence of ctDNA, either pre-operatively or at any time post-operatively, was associated with inferior relapse-free survival (HR = 2.70, P = .046; HR = 3.23, P = .003, respectively). Among patients who were ctDNA positive at any time point, the sensitivity of relapse prediction was 84% with a PPV of 90%. Of note, ctDNA positivity at a post-surgical time point revealed a PPV of 100% and NPV of 64%. The lack of ctDNA detection at both time points yielded an NPV of 80%. CONCLUSIONS: Detection of plasma ctDNA using a personalized assay is prognostic of recurrence in patients with resected RCC. Herein, we describe a successful approach for its application and identify potential limitations to be addressed in future studies.

Financial Distress in Genitourinary Cancer: Insights From CDC National Health Interview Survey.

PURPOSE: This study leverages CDC National Health Interview Survey data to examine Financial Distress (FD) among genitourinary (GU) cancer survivors, specifically prostate cancer (PC), kidney cancer (KC), and bladder cancer (BC). It investigates the economic impacts faced by these patients, especially in relation to disparities in insurance coverage and its effects on material, psychological, and behavioral aspects of FD. METHODS: We retrospectively analyzed responses from GU cancer survivors, stratifying by cancer status and age (18-64 years, ≥65 years). Medical financial hardship was divided into three domains: material, psychological, and behavioral. Associations between cancer history, hardship, and clinical factors were assessed using generalized ordinal logistic regressions. RESULTS: Significant health care access disparities were found, particularly for mental health services, with 25% of younger BC survivors and 4.7% of younger KC survivors reporting affordability issues, in contrast to 2.7% of noncancer individuals. Dental care was also problematic, with higher avoidance rates among younger BC (27%) and KC (15%) survivors compared with the general population. Surprisingly, noncancer individuals reported more difficulty in affording prescriptions than BC survivors across both age groups. PC survivors, however, showed lower FD across all domains versus noncancer controls, indicating fewer concerns about medical bills and a lesser tendency to forgo care. CONCLUSION: The study underscores significant gaps in the financial support system for GU cancer survivors, with urgent needs in mental and dental health care access. Policy interventions, including comprehensive insurance reforms, are imperative to alleviate the financial burdens on these individuals.

Adjuvant Atezolizumab in Patients with Sarcomatoid Renal Cell Carcinoma: A Prespecified Subgroup Analysis of IMmotion010.

Patients with sarcomatoid renal cell carcinoma (sRCC) have a poor prognosis. In the randomised, double-blind phase 3 IMmotion010 trial (NCT03024996), adjuvant atezolizumab did not demonstrate a disease-free survival (DFS) benefit versus placebo in the overall population of patients with locoregional renal cell carcinoma with an increased risk of recurrence following surgery. This prespecified subgroup analysis of efficacy and safety was completed in 104 patients with sRCC. Baseline characteristics were similar between treatment arms. At a median follow-up of 45 mo, the median DFS was not evaluable (NE; 95% confidence interval [CI], 12 mo-NE) in the atezolizumab arm (n = 37) and 23 mo (95% CI, 11-NE) in the placebo arm (n = 66; hazard ratio 0.77 [95% CI, 0.44-1.4]). In the sRCC subgroup, grade 3/4 treatment-related adverse events (TRAEs) occurred in one patient (2.7%) in the atezolizumab arm and two patients (3.0%) in the placebo arm. By comparison, 54 of 353 patients (15%) and 16 of 317 patients (5.0%) with non-sarcomatoid histology reported grade 3/4 TRAEs in the respective arms. In conclusion, the difference in DFS was not statistically significant between adjuvant atezolizumab and placebo in patients with sRCC. The safety profile was similar between patients with sRCC and non-sRCC. PATIENT SUMMARY: Patients with a specific type of locoregional kidney cancer (tumours with sarcomatoid features) were treated with atezolizumab or placebo after surgery. Slightly more patients treated with atezolizumab lived longer without the disease getting worse than those treated with placebo, although this finding was not statistically significant. The side effects were similar to those seen in patients with other types of kidney cancer treated with atezolizumab in the same study (IMmotion010). In patients with sarcomatoid kidney cancer, atezolizumab was tolerable and may be more effective than placebo, but this requires further study.

Urine Biopsy as Dynamic Biomarker to Enhance Clinical Staging of Bladder Cancer in Radical Cystectomy Candidates.

PURPOSE: There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing-based molecular assay using urine to enhance clinical staging of patients with bladder cancer. METHODS: Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination. RESULTS: First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662, n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort. CONCLUSION: MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Preoperative Physical Therapy is Associated with Decreased Length of Stay and Improved Postoperative Mobility in Patients with Sarcopenia Undergoing Adult Spinal Deformity Surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the relationship between preoperative physical therapy (PT) and postoperative mobility, adverse events (AEs), and length of stay (LOS) among patients with low normalized total psoas area (NTPA) undergoing ASD surgery. SUMMARY OF BACKGROUND DATA: Sarcopenia as defined by low NTPA has been shown to predict poor perioperative outcomes following adult spinal deformity (ASD) surgery. However, there is limited evidence correlating the benefits of PT within the sarcopenic patient population. METHODS: NTPA was analyzed at the L3 and L4 mid-vertebral body on preoperative magnetic resonance imaging (MRI). Receiver operating characteristic (ROC) curve analysis was used to determine gender-specific NTPA cut-off values for predicting perioperative AEs. Patients were categorized as having low NTPA if both L3 and L4 NTPA were below these cut-off values. Perioperative outcomes were compared between patients with low NTPA that underwent documented formal PT within 6 months prior to ASD surgery with those that did not. RESULTS: 103 patients (42 males, 61 females) met criteria for low NTPA for inclusion in the study, of which 42 underwent preoperative PT and 61 did not. The preoperative PT group had a shorter LOS (111.2±37.5 vs. 162.1±97.0 h, P<0.001), higher ambulation distances (feet) on postoperative day (POD) 1 (61.7±50.3 vs. 26.1±69.0, P<0.001), POD 2 (113.2±81.8 vs. 62.1±73.1, P=0.003), and POD 3 (126.0±61.2 vs. 91.2±72.6, P=0.029), and lower rates of total AEs (31.0% vs. 54.1%, P=0.003) when excluding anemia requiring transfusion. Multivariable analysis found preoperative PT to be the most significant predictor of decreased LOS (OR 0.32, P=0.013). CONCLUSION: Sarcopenic patients may benefit from formal preoperative PT prior to undergoing ASD surgery to improve early postoperative mobility, decrease AEs, and decrease LOS. LEVEL OF EVIDENCE: 3.